title: In silico study of desmosdumotin as an anticancer agent: homology modeling, docking and molecular dynamics simulation approach.
abstract: P-glycoprotein (P-gp) is responsible for the multidrug resistance (MDR) and involved in the expulsion of xenobiotics out of cell. In this paper, homology modeling, docking and molecular dynamics simulation (MDS) was performed for the human P-gp desmosdumotin inhibitor. Docking study was carried out in the P-gp nucleotide binding domain 2 (NBD2). The desmosdumotin binding region occupied the ATP binding region (flavonoid binding region) with hydrophobic and hydrophilic interactions. Analysis of root mean square deviations (RMSDs) of active site residues indicated the binding site residues were stable throughout the simulation period. As shown in previous results with structurally similar flavonoid compounds, van der Waals and electrostatic interactions were found to be important factors for the desmosdumotin-NBD2 inhibition. Docking results suggest that desmosdumotin interacts with the NBD2 through both hydrogen bonds (Lys1076, Ser1077 and Thr1078) and hydrophobic interactions (Tyr1044, Val1052, Gly1073 and Cys1074). In addition, the involvement of other amino-acids was identified via MDS (Lys1076 and Ser1077 for hydrogen bonds and Tyr1044, Val1052, Gly1073, Cys1074 and Gly1075 for hydrophobic interactions). Thus, current preliminary model of interactions between desmosdumotin-NBD2 could be helpful to understand the in-depth inhibition mechanism of P-gp at NBD2 level and to design more potent inhibitors which could effectively overcome MDR of anticancer agents.
authors.forename: Changdev G
authors.initials: CG
authors.lastname: Gadhe
authors.forename: Gugan
authors.initials: G
authors.lastname: Kothandan
authors.affiliation: College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu Gwangju 501-759, Republic of Korea. chosj@chosun.ac.kr.
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Cho
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry*; D000475:Alkenes / Q000737:chemistry*; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry*; D020134:Catalytic Domain; D030562:Databases, Protein; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007659:Ketones / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment; D055672:Static Electricity; D040681:Structural Homology, Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000475:Alkenes; D000970:Antineoplastic Agents; D007659:Ketones; C073119:TAP1 protein, human; C502470:desmosdumotin C